Background: Obesity affects 36% of US women and men and increases lifetime risk for diabetes and cardiovascular disease. Similarly, depression affects 20% of US women and 13% of men and is the leading cause of disability worldwide. Further, the 2 disorders have a bidirectional positive relationship. Proven behavioral interventions to treat obesity and depression exist; however, the underlying biological mechanisms remain unknown. This lack of understanding significantly hampers efforts to optimize the effectiveness of behavioral interventions and limits their dissemination and implementation into widespread practice to curtail the adverse consequences of obesity and depression and promote population health. Rapid advances in human neuroscience and behavioral science and integration of the two could provide unique opportunity to fill this gap. Objective: Leveraging a recently funded 2-year randomized controlled trial (RAINBOW target n=404; PI Dr. Jun Ma) of a first-ever integrated treatment for comorbid obesity and depression in primary care that uniquely combines 2 nationally recognized behavioral interventions, we propose a 2-phased project to identify, validate and refine a set of assays to measure self-regulation targets; and to engage these targets to optimize behavioral treatment of obesity and depression. Specific Aims: In the UH2 phase, we will (1) Conduct secondary data analysis and hold workshops and a symposium to finalize selection of self-regulation targets and assays for testing; (2) Leverage the RAINBOW intervention to engage identified targets; and (3) Verify target engagement across multiple domains (neural, physiological, behavioral, psychological), settings (laboratory, virtual, and naturalistic), and time points (0, 4 weeks, 6, 12 and 24 months) Transitional milestones are to (1) Establish assay(s) that reliably and accurately measure the identified targets; (2) Demonstrate malleability of the self-regulation target(s) in response to th RAINBOW integrated treatment; and (3) Identify self-regulation profile(s) that predict treatment response in health behaviors (medical regimen adherence, physical activity, diet) and outcomes (weight, depression). In the UH3 phase, we will conduct a pilot randomized controlled trial in which an additional 100 obese and depressed adults will be randomized to intervention or wait-list control and assessed at baseline, 4 weeks and 6 months. Intervention subjects will receive the first 4 weeks of the RAINBOW intervention, followed by target-guided tailoring of the intervention components in order to optimize target engagement and enhance behavioral change based on their individual self-regulation profile during the first 4 weeks. We will use the insights from intervention subjects to then further refine the tailoring strategies for the waitlis subjects. Implications: This research will provide a toolkit of well-validated assays of self-regulation targets important for health behavior change, as well as target- guided personalization of intervention strategies, in the treatment of comorbid obesity and depression. Impact: Given the widespread relevance of these disorders and the targeted health behaviors, this research will be a prototype for treating multiple chronic conditions with profound potential impacts on population health.